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Manipulating niche composition limits damage to haematopoietic stem cells during Plasmodium infection

by Lo, Celso Cristina , Duffy, Ken R , Göttgens Berthold , Blagborough, Andrew M , Ang, Heather , Wilson, Nicola K , Eilers Kira , Ruivo Nicola , Birch, Flora , Watcham Samuel , Langhorne, Jean , Sinden, Robert E , Anton Sara Gonzalez , Pirillo Chiara , Haltalli, Myriam L , Luis, Tiago C , Lipien Alexander , Vainieri, Maria L , Constandina, Pospori

in Animal models / Biomedical materials / Bone marrow / Cell proliferation / Endothelial cells / Gene sequencing / Hematopoietic stem cells / Infections / Integrity / Interferon / Malaria / Mathematical models / Mesenchyme / Niches / Osteoblasts / Parathyroid / Parathyroid hormone / Reactive oxygen species / Ribonucleic acid / RNA / Stem cell transplantation / Stem cells / Transplantation / Vector-borne diseases

2020

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Manipulating niche composition limits damage to haematopoietic stem cells during Plasmodium infection

2020

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Manipulating niche composition limits damage to haematopoietic stem cells during Plasmodium infection

2020

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Journal Article

Manipulating niche composition limits damage to haematopoietic stem cells during Plasmodium infection

Lo, Celso Cristina,

Duffy, Ken R,

Göttgens Berthold,

Blagborough, Andrew M,

Ang, Heather,

Wilson, Nicola K,

Eilers Kira,

Ruivo Nicola,

Birch, Flora,

Watcham Samuel,

Langhorne, Jean,

Sinden, Robert E,

Anton Sara Gonzalez,

Pirillo Chiara,

Haltalli, Myriam L,

Luis, Tiago C,

Lipien Alexander,

Vainieri, Maria L,

Constandina, Pospori

2020

Overview

Severe infections are a major stress on haematopoiesis, where the consequences for haematopoietic stem cells (HSCs) have only recently started to emerge. HSC function critically depends on the integrity of complex bone marrow (BM) niches; however, what role the BM microenvironment plays in mediating the effects of infection on HSCs remains an open question. Here, using a murine model of malaria and combining single-cell RNA sequencing, mathematical modelling, transplantation assays and intravital microscopy, we show that haematopoiesis is reprogrammed upon infection, whereby the HSC compartment turns over substantially faster than at steady-state and HSC function is drastically affected. Interferon is found to affect both haematopoietic and mesenchymal BM cells and we specifically identify a dramatic loss of osteoblasts and alterations in endothelial cell function. Osteo-active parathyroid hormone treatment abolishes infection-triggered HSC proliferation and—coupled with reactive oxygen species quenching—enables partial rescuing of HSC function.Haltalli et al. show that Plasmodium berghei infection induces interferon release, and affects haematopoietic stem cell proliferation and function, as well as osteoblasts and vascular integrity, in the bone marrow niche.

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Publisher

Nature Publishing Group

Subject

Animal models

/ Biomedical materials

/ Hematopoietic stem cells